Preparation method of oxaggolil sodium impurity I
By using valeric acid or Oxone as an oxidant in the oxalic acid oxalic acid reaction and combining pH adjustment and liquid separation treatment, high-purity oxalic acid impurities were successfully prepared, and the conversion rate in the prior art was solved The problem of low and product impurities achieves an efficient and low-cost preparation process.
Patent Information
- Application Number
- CN202411589185.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-08
- Publication Date
- 2024-12-27
AI Technical Summary
The existing Olagoli sodium oxidized impurities preparation method has low conversion rate and relatively complex products, requiring high-cost liquid phase separation, which is not suitable for large-scale preparation.
Using valeric acid or Oxone as oxidant, the oxalolic sodium is oxidized in the reaction solvent, and the solution is separated by adjusting the pH value and adding sodium chloride, drying with anhydrous sodium sulfate and crystallization with benign solvents, combined with activated carbon Decolorization, filtering and drying to give oxalgoli sodium oxidized impurities.
The preparation of oxadol sodium oxidized impurities with high selectivity and high yield is achieved, with a purity of more than 99%, low cost and simple operation, and avoiding complex column chromatography and liquid phase purification processes.
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Figure CN119192090A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of chemical synthesis and relates to a method for preparing an impurity of elagolid sodium, and specifically relates to a method for preparing an oxidized impurity of elagolid sodium having a structure as shown in formula I. Background Art
[0002] Elagolix Sodium (Orilissa, chemical name (R)-4-[[2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)-benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]amino]butyrate sodium) was jointly developed by AbbVie and Neurocrine Biosciences Inc. and approved by the US FDA for marketing on July 24, 2018. It is an effective, selective, and orally bioactive second-generation non-peptide gonadotropin-releasing hormone receptor antagonist, clinically suitable for the treatment of endometriosis (EMs) and the relief of its associated moderate to severe pain symptoms. Elagolix Sodium has strong stability in the body, is not easily enzymatically hydrolyzed, and has mild adverse reactions. It is an important breakthrough in the treatment of this indication in the past 10 years.
[0003] The impurities of elegans sodium are of great significance for the in-depth study of elegans sodium.
[0004] Chinese invention patent application CN111499581A reports that three oxidized impurities of elagolid sodium (structures are shown in formulas Ⅰ, Ⅱ, and Ⅲ, respectively) are prepared using elagolid sodium as a raw material and oxidized with hydrogen peroxide. However, the conversion rate of this preparation method is low, and the reaction products are relatively complex, requiring separation by a preparative liquid phase method, which is costly and not suitable for large-scale preparation.
[0005] Summary of the invention
[0006] The purpose of the present invention is to provide a method for preparing an impurity of elagolid sodium having a structure as shown in formula I, and to provide an impurity reference substance for quality research of elagolid sodium.
[0007] Elagoli sodium (Compound EL), chemical name is (R)-sodium 4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)amino)butyrate.
[0008] The impurity of elagolide sodium shown in Formula I has a chemical name: sodium (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)(hydroxy)amino)butyrate.
[0009] The technical solution of the present invention is as follows:
[0010] A method for preparing an oxidized impurity of elagolid sodium shown in formula I, the synthetic route is as follows:
[0011]
[0012] The method comprises: using pivalic acid or Oxone as an oxidant, and allowing sodium elagolid and the oxidant to undergo an oxidation reaction in a reaction solvent; after the reaction is completed, adding an oxidation terminator to terminate the reaction, adjusting the pH value of the reaction solution to 9-11 with an alkali solution, adding sodium chloride to saturation, separating the liquids, collecting the organic layer, drying the organic layer over anhydrous sodium sulfate, concentrating to dryness, adding a benign solvent to dissolve, then adding a poor solvent, crystallizing, filtering, and drying to obtain the sodium elagolid impurity product shown in formula I.
[0013] The molar ratio of elagolid sodium to the oxidant is 1:1.0 to 1:3.0, preferably 1:1.2 to 1:1.5.
[0014] The Chinese name of Oxone is potassium persulfate complex salt, which is a ternary salt composed of 2KHSO5, KHSO4 and K2SO4.
[0015] The oxidation reaction temperature is 0 to 100° C., preferably 10 to 40° C., more preferably 20 to 35° C.; the oxidation reaction time is 1 minute to 24 hours, preferably 0.5 hours to 12 hours, more preferably 1.5 hours to 2 hours.
[0016] The amount of the reaction solvent used will affect the yield of the product. The mass volume ratio of the elagolid sodium to the reaction solvent is 1:1 to 1:10 g / ml, preferably 1:6 to 1:7.5 g / ml.
[0017] The reaction solvent is one or more of water, ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, isopropyl acetate, dichloromethane and the like, preferably a mixed solvent of water and at least one organic solvent selected from dichloromethane, tetrahydrofuran and acetonitrile in a volume ratio of 1:3 to 3:1, more preferably a mixed solvent of water and at least one organic solvent selected from dichloromethane, tetrahydrofuran and acetonitrile in a volume ratio of 1:3 to 1:2.
[0018] Specifically, the reaction solvent is a mixed solvent of water and dichloromethane in a volume ratio of 1:2, a mixed solvent of water and tetrahydrofuran in a volume ratio of 1:3, or a mixed solvent of water, dichloromethane and acetonitrile in a volume ratio of 1:1:1.
[0019] The oxidation terminator is a sodium thiosulfate solution or a sodium bisulfite solution, preferably a sodium bisulfite solution. The concentration of the sodium thiosulfate solution is 10% to 40% (mass volume ratio), and the concentration of the sodium bisulfite solution is 10% to 40% (mass volume ratio), preferably 20% to 30%.
[0020] The alkaline solution is a sodium carbonate solution, a sodium bicarbonate solution or a hydroxide solution, preferably a saturated sodium carbonate solution, a saturated sodium bicarbonate solution or a sodium hydroxide solution with a mass fraction of 10% to 40%.
[0021] The mass volume ratio of elagolid sodium to the benign solvent is 1:1 to 1:8 g / ml, preferably 1:1.5 to 1:4 g / ml, and more preferably 1:1.5 to 1:2 g / ml.
[0022] The volume ratio of the good solvent to the poor solvent is 1:1 to 1:20, preferably 1:5 to 1:10.
[0023] The good solvent can be selected from but not limited to one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, and isopropyl acetate, preferably at least one of ethyl acetate and isopropyl acetate; the poor solvent can be selected from but not limited to one or more of methyl tert-butyl ether, isopropyl ether, n-hexane, and n-heptane, preferably at least one of n-hexane and n-heptane.
[0024] The crystallization temperature is 0±5° C. The crystallization is performed under stirring.
[0025] As a preferred technical solution of the present invention, a good solvent is added to dissolve, activated carbon is added to decolorize, filtered, and a poor solvent is added to the filtrate.
[0026] The mass ratio of elagolid sodium to activated carbon is 20:1 to 20:2. The decolorization time of activated carbon is 5 to 15 minutes.
[0027] As a preferred embodiment of the method for preparing the oxidized impurity of elagolix sodium represented by formula I described in the present invention, when the reaction solvent is a mixed solvent of water and a water-insoluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 9-11 with an alkaline solution, solid sodium chloride is added to saturation, the liquids are separated, and the organic layer is collected.
[0028] The non-water-soluble solvent is selected from at least one of ethyl acetate, isopropyl acetate, dichloromethane and the like.
[0029] As a preferred embodiment of the method for preparing the oxidized impurity of elagolix sodium represented by formula I described in the present invention, when the reaction solvent is a mixed solvent of water and a water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 9-11 with an alkaline solution, solid sodium chloride is added to saturation, an extraction solvent is added, the liquids are separated, and the organic layer is collected.
[0030] The water-soluble solvent is selected from at least one of tetrahydrofuran, acetone, acetonitrile, ethanol, methanol and the like.
[0031] The extraction solvent is ethyl acetate, dichloromethane or isopropyl acetate; the volume ratio of the extraction solvent to the water-soluble solvent is 1:1.
[0032] Specifically, when the reaction solvent is a mixed solvent of water and a non-water-soluble solvent, after the reaction is completed, an oxidative terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 9-11 with an alkaline solution, sodium chloride solid is added to saturation, the liquids are separated, the organic layer is collected, the organic layer is dried over anhydrous sodium sulfate, and then concentrated to dryness; a benign solvent is added to dissolve at a temperature of 20-40°C, activated carbon is added for decolorization, filtered, a poor solvent is added to the filtrate, cooled to 0±5°C, stirred for crystallization, filtered, and dried to obtain the sodium aragolide impurity product shown in formula I.
[0033] When the reaction solvent is a mixed solvent of water and a water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 9-11 with an alkaline solution, sodium chloride solid is added to saturation, an extraction solvent is added, the liquids are separated, the organic layer is collected, the organic layer is dried over anhydrous sodium sulfate, and then concentrated to dryness; a good solvent is added to dissolve at a temperature of 20-40°C, and activated carbon is added for decolorization, and the mixture is filtered, a poor solvent is added to the filtrate, and the mixture is cooled to 0±5°C, stirred for crystallization, filtered, and dried to obtain the impurity product of elagolid sodium shown in Formula I.
[0034] Another object of the present invention is to provide the use of the impurity of elagolid sodium shown in formula I in the inspection of related substances of elagolid sodium and quality research; for example, it can be used as an impurity reference substance for quality research of elagolid sodium.
[0035] Compared with the prior art, the present invention has the following beneficial effects:
[0036] The present invention avoids the use of hydrogen peroxide, meta-chloroperbenzoic acid and the like as oxidants, which results in a more complex reaction product and the need for purification by complex and costly methods such as column chromatography and preparative liquid phase.
[0037] The invention can be used for the directional preparation of the oxidized impurity I of elagolix sodium, has a short reaction route, mild reaction conditions, simple operation and simple post-treatment; and has high safety and low cost in the entire reaction process.
[0038] The method of the present invention is used to prepare the oxidized impurity I of elagolix sodium, with high selectivity, a yield of more than 95%, and a purity of more than 99%.
[0039] The invention has important significance for the quality research and process control of elagolid sodium. BRIEF DESCRIPTION OF THE DRAWINGS
[0040] Figure 1 is the H NMR spectrum of compound Ⅰ ( 1 1H NMR).
[0041] Figure 2 This is the mass spectrum of compound Ⅰ. DETAILED DESCRIPTION
[0042] The technical scheme of the present invention is further illustrated by the following examples, which are only used to more specifically illustrate the preferred embodiments of the present invention and are not used to limit the technical scheme of the present invention. Any method and material similar or equivalent to the contents contained herein can be used in the present invention. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art.
[0043] The experimental methods in the following examples without specifying specific conditions were generally prepared according to conventional conditions.
[0044] Example 1
[0045] Preparation of Compound Ⅰ
[0046] Add elelagoli sodium (compound EL, 20.0 g, 30.6 mmol), Oxone (22.59 g, 36.75 mmol), water (50 ml) and dichloromethane (100 ml) into a three-necked flask, stir to dissolve, and stir to react at 30 ± 2 ° C for 2 h; after the reaction is completed, add 30% sodium bisulfite solution (10 ml) and stir for 10 min to terminate the reaction, adjust the pH value of the reaction solution to 10 with 30% sodium hydroxide solution, and then add chloride Sodium solid was added to saturation, and the liquid was separated. The organic layer was collected. After the organic layer was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to dryness; 40 ml of ethyl acetate was added to dissolve at room temperature, and 1.0 g of activated carbon was added. The mixture was decolorized at room temperature for 5 min, and filtered. 400 ml of n-hexane was added to the filtrate at room temperature, and the system was cooled to 0±5°C, stirred and crystallized for 2 h. A large amount of solid was precipitated. It was filtered and dried to obtain compound I product (light yellow solid, 19.82 g, yield 96.73%, HPLC purity 99.1%). 1H NMR (400MHz, DMSO-d6) δ: 7.51(m,3H,Ar-H), 7.12(m,7H,Ar-H), 6.48(m,1H,Ar-H), 5.33(s,2H,CH2), 4.22(m,1H,-OH), 3.93(m,1 H,-CH), 3.85(s,3H,-CH3), 2.78(m,2H,-CH2), 2.19(m,2H,-CH2), 2.05(s,3H,-CH3), 1.59(m,2H,-CH2), 1.24(m,2H,-CH2); TOFMS ES(+)(m / z): 648.3[M-Na+H] + ).
[0047] Example 2
[0048] Preparation of Compound Ⅰ
[0049] Add elagolix sodium (Compound EL, 20.0 g, 30.6 mmol), pivalic acid (4.02 g, 39.36 mmol), water (30 ml) and tetrahydrofuran (90 ml) into a three-necked flask, stir to dissolve, and stir to react at 25±2°C for 2 h. After the reaction, add 20% sodium bisulfite solution (20 ml) and stir for 10 min to terminate the reaction. Adjust the pH value of the reaction solution to 10 with 20% sodium hydroxide solution, add sodium chloride solid to saturation, and then add acetic acid isocyanate. 90 ml of propyl ester was added for extraction and separation, and the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness; 40 ml of ethyl acetate was added to dissolve at room temperature, and 1.0 g of activated carbon was added. The mixture was decolorized at room temperature for 10 min, and filtered. 400 ml of n-heptane was added to the filtrate at room temperature, and the system was cooled to 0±5°C, stirred and crystallized for 3 h. A large amount of solid was precipitated. It was filtered and dried to obtain compound I product (light yellow solid, 19.61 g, yield 95.71%, HPLC purity 99.2%).
[0050] Example 3
[0051] Preparation of Compound Ⅰ
[0052] Add elagolix sodium (Compound EL, 20.0 g, 30.6 mmol), Oxone (26.32 g, 42.81 mmol), water (50 ml), dichloromethane (50 ml) and acetonitrile (50 ml) into a three-necked flask, stir to dissolve, and stir to react at 30±2°C for 1.5 h. After the reaction is completed, add 20% sodium bisulfite solution (15 ml) and stir for 10 min to terminate the reaction. Adjust the pH value of the reaction solution to 9.5 with saturated sodium carbonate solution, and then add sodium chloride solid to saturate. And, then add 50 ml of dichloromethane, extract and separate the liquids, collect the organic layer, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness; at room temperature, add 30 ml of isopropyl acetate to dissolve, and add 1.0 g of activated carbon, decolorize at room temperature for 10 minutes, filter, add 300 ml of n-heptane to the filtrate at room temperature, cool the system to 0±5°C, stir and crystallize for 2 hours, a large amount of solid precipitates, filter, and dry to obtain compound I product (light yellow solid, 19.97 g, yield 97.46%, HPLC purity 99.2%).
Claims
1. A method for preparing the oxidized impurities of elagolid sodium represented by formula I, characterized in that: The synthetic route is as follows: The method comprises: using pivalic acid or Oxone as an oxidant, and allowing sodium elagolid and the oxidant to undergo an oxidation reaction in a reaction solvent; after the reaction is completed, adding an oxidation terminator to terminate the reaction, adjusting the pH value of the reaction solution to 9-11 with an alkali solution, adding sodium chloride to saturation, separating the liquids, collecting an organic layer, drying the organic layer over anhydrous sodium sulfate, concentrating to dryness, adding a benign solvent to dissolve, then adding a poor solvent, crystallizing, filtering, and obtaining the sodium elagolid impurity shown in formula I.
2. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The molar ratio of elagolid sodium to the oxidant is 1:1.0 to 1:3.0, preferably 1:1.2 to 1:1.
5.
3. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The oxidation reaction temperature is 0 to 100° C., preferably 10 to 40° C., more preferably 20 to 35° C.; the oxidation reaction time is 1 minute to 24 hours, preferably 0.5 hours to 12 hours, more preferably 1.5 hours to 2 hours.
4. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The mass volume ratio of elagolid sodium to the reaction solvent is 1:1 to 1:10 g / ml, preferably 1:6 to 1:7.5 g / ml.
5. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The reaction solvent is one or more of water, ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, isopropyl acetate, and dichloromethane, preferably a mixed solvent of water and at least one organic solvent selected from dichloromethane, tetrahydrofuran, and acetonitrile in a volume ratio of 1:3 to 3:
1.
6. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The oxidation terminator is sodium thiosulfate solution or sodium bisulfite solution; the alkaline solution is sodium carbonate solution, sodium bicarbonate solution or hydroxide solution.
7. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: When the reaction solvent is a mixed solvent of water and a non-water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 9-11 with an alkaline solution, sodium chloride solid is added to saturation, the liquids are separated, and the organic layer is collected; the non-water-soluble solvent is selected from at least one of ethyl acetate, isopropyl acetate, and dichloromethane; When the reaction solvent is a mixed solvent of water and a water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 9-11 with an alkaline solution, solid sodium chloride is added to saturation, an extraction solvent is added, the liquids are separated, and the organic layer is collected; the water-soluble solvent is selected from at least one of tetrahydrofuran, acetone, acetonitrile, ethanol, and methanol; the extraction solvent is ethyl acetate, dichloromethane or isopropyl acetate; the volume ratio of the extraction solvent to the water-soluble solvent is 1:
1.
8. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The mass volume ratio of the elagolid sodium to the benign solvent is 1:1 to 1:8 g / ml, preferably 1:1.5 to 1:4 g / ml, and more preferably 1:1.5 to 1:2 g / ml; the volume ratio of the benign solvent to the poor solvent is 1:1 to 1:20, preferably 1:5 to 1:10; the benign solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, and isopropyl acetate, preferably at least one of ethyl acetate and isopropyl acetate; the poor solvent is selected from one or more of methyl tert-butyl ether, isopropyl ether, n-hexane, and n-heptane, preferably at least one of n-hexane and n-heptane.
9. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The crystallization temperature is 0±5°C.
10. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: Add a good solvent to dissolve, then add activated carbon to decolorize, filter, and add a bad solvent to the filtrate.